Alder BioPharmaceuticals: Fifteen Years in the Making – CGRP Therapy Breaks New Ground in Migraine Treatment

“All you can do is go into a dark room and pray for it to stop.”

This sentence, along with other similar ones, is printed on the walls of Alder BioPharmaceuticals (hereinafter referred to as “Alder”).

In 2019, Alder was acquired by the Danish pharmaceutical company Lundbeck for $1.95 billion. That same year, Alder was named one of the 100 fastest-growing companies in the United States. To provide insights for entrepreneurs in China, VCBeat has reviewed Alder’s development trajectory.

Alder, founded in 2004 and headquartered in Washington, USA, is a clinical-stage biotechnology and pharmaceutical company. The company is dedicated to the discovery, development, and commercialization of novel therapeutic antibodies to transform migraine treatment paradigms.

Alder’s original intent and mission are to disrupt migraine treatment paradigms, enabling patients to return to normal lives. This mission is deeply rooted in the prior experiences of Alder’s three founders.

Alder’s three founders—Dr. Randall C. Schatzman, Dr. John A. Latham, and Dr. Mark J. Litton—were each motivated by personal reasons to pursue novel therapies for migraine. All three doctors’ wives suffered from migraines, and they recognized that existing migraine medications were associated with numerous adverse effects, such as vomiting, palpitations, addiction, and peripheral vasoconstriction, while offering limited therapeutic efficacy.

John Latham said, “During college, I couldn’t understand why my girlfriend couldn’t make it to class on time. It was only later that I learned she was sidelined by migraines at least once a week. At that moment, I resolved that if given the opportunity in the future, I would do something for those dearest to my heart.”

By a stroke of serendipity, the three of them joined the same company and exchanged ideas on migraine treatment regimens. In light of the challenges plaguing the migraine treatment market, they resolved to make their mark in this field. However, the immediate obstacles they faced were securing funding, premises, and equipment. Meanwhile, they lacked experience in entrepreneurship and management.

Fortunately, they met Clay Siegall, the founder, president, CEO, and chairman of Seattle Genetics, a publicly listed biopharmaceutical company focused on cancer.

“Incubating startups is not our focus. But if there’s an opportunity to help a startup that isn’t focused on oncology, and they respect and recognize us, Seattle Genetics might consider doing it once,” said Clay Siegall in an interview.

Before Alder was founded, its three founders consulted Clay Siegall. Starting with advice on how to establish Seattle Genetics, the trio continually sought guidance on entrepreneurial and management experience. “One answer usually led to more questions, so we arranged regular meetings,” said Siegall. When they discussed their lack of funding, equipment, and office space, I suggested that they try using a space at Seattle Genetics.

To express gratitude to Clay Siegall, Alder granted him a portion of its shares. When Alder went public on the Nasdaq on May 9, 2014, it raised $80 million. Over the following four years, Alder’s market capitalization exceeded $1 billion, thereby yielding substantial returns for Clay Siegall.

Migraine is a chronic neurovascular disorder affecting 1.3 billion people worldwide. The prevalence in women is three times that in men. Migraine is characterized primarily by severe unilateral headache, often accompanied by comorbidities such as nausea, vomiting, and sensitivity to sound and light.

The age group with the highest incidence of migraine is 35–39 years, and approximately 20% of migraine patients experience aura symptoms. According to data released by the World Health Organization, individuals suffering from migraine or other severe headaches miss an average of 7 days of work or activities per year.

Moreover, individuals with chronic migraine experience more than three times as many days of impaired normal activity compared to those with less frequent migraine attacks. Migraine sufferers may also encounter other issues outside of acute episodes, such as fatigue and emotional or mental health problems. Consequently, migraine imposes a substantial burden on society, the economy, and individuals. According to a U.S.-based foundation, the medical costs and productivity losses associated with migraine in the United States are estimated to reach as high as $36 billion.

For a long time, pharmacological treatment for migraine remained in a state of equilibrium with few breakthroughs, until the approval of the first preventive migraine medication in 2018 broke the stalemate of no progress since 2010.

Previously, preventive treatment for migraine was limited by safety, efficacy, and tolerability concerns, failing to meet the needs of most patients. Preventive therapy for migraine may require weeks to months to achieve meaningful clinical benefits. Due to lack of efficacy or excessive side effects, most patients are unable to maintain long-term medication use.

Now that the transition period has arrived, the migraine drug market will face further changes. It is expected that more drugs for the prevention and acute treatment of migraine will be launched in the next five years.

Breakthroughs in the pharmacological treatment of migraine are inseparable from calcitonin gene-related peptide (CGRP). CGRP is a potent vasodilatory neuropeptide; upon release, it induces local vasodilation and the extravasation of plasma and plasma proteins into surrounding tissues. Studies have shown that intravenous administration of CGRP can trigger migraines in susceptible individuals (while blocking CGRP can alleviate migraine symptoms). At the time, Merck & Co., then an industry leader, terminated its CGRP therapeutic research program, but other companies subsequently joined the effort, gradually heating up this field of research.

In 2018, three CGRP monoclonal antibody drugs—Amgen/Novartis’s Aimovig (erenumab), Eli Lilly’s Emgality (galcanezumab), and Pfizer/Teva’s Ajovy (fremanezumab)—were approved for marketing in the United States and have been widely used in the European market. Following closely behind is Alder BioPharmaceuticals’ eptinezumab, which is currently under review by the U.S. FDA.

Alder’s optimism regarding the FDA approval of eptinezumab is evident from its large-scale recruitment of sales personnel.

Alder President and Chief Executive Officer Bob Azelby stated, “We expect to achieve significant progress in the first quarter of 2020, with the anticipated U.S. launch of eptinezumab (approved for marketing). We presented additional evidence at the 2019 annual meetings of the American Headache Society and the American Academy of Neurology, further corroborating eptinezumab’s distinct clinical profile and benefits in patient-reported outcomes.”

Eptinezumab is a new drug developed by Alder over 15 years for the prevention of migraine. This agent exhibits high specificity and strong binding affinity, inhibiting calcitonin gene-related peptide (CGRP). If approved by the FDA, it will be the first intravenous therapy for migraine prevention.

Bob Azelby, CEO of Alder Biopharmaceuticals, stated, “Completed clinical trials have demonstrated that eptinezumab, administered as a 30-minute intravenous infusion every three months, reduces the frequency of migraine attacks to varying degrees over a 12-week period.”

It is understood that eptinezumab is one of the few preventive medications targeting the specific protein calcitonin gene-related peptide (CGRP), with similar products including erenumab, fremanezumab, and galcanezumab. While these four CGRP antibodies exhibit comparable efficacy and tolerability, they are not without differences.

One difference is that erenumab and galcanezumab are administered via subcutaneous injection once monthly and can be used at home with prefilled autoinjectors; fremanezumab is administered via subcutaneous injection once monthly or quarterly, but only prefilled syringes are available; whereas eptinezumab is administered via intravenous infusion once quarterly.

On the other hand, compared with traditional migraine medications, CGRP therapies can effectively treat migraine patients who have failed preventive treatment due to efficacy or tolerability issues. Such drugs also exhibit excellent tolerability and safety profiles. To date, apart from hypersensitivity reactions, the FDA has not required any additional adverse reaction warnings for marketed drugs in this class. In clinical trials or treatment cases, hypersensitivity reactions have occurred only at the injection site.

Bob Azelby stated, “Developing any new prescription drug is difficult and costly.” Alder Biopharmaceuticals did not disclose how much it spent on the development of eptinezumab. However, according to estimates from Tufts University research, pharmaceutical companies spend an average of $2.6 billion to develop a new drug, from clinical trials through FDA approval.

Bob Azelby, reflecting on the early days of his startup, said, “There were always days when I felt like I couldn’t go on. I racked my brains trying to figure out how to pay next month’s salaries.” Dr. John Latham stated, “We went 24 months without paying ourselves any salary. We told our wives that we wouldn’t have any income for a while. To cover daily living expenses, I relied on credit cards (borrowing).”

Heather Malcolm, Vice President of Human Resources at Alder Biopharmaceuticals, experiences 9 to 12 migraine attacks per month. She hopes that eptinezumab will help migraine sufferers, including herself, find relief from their suffering. “My dream is to be the first patient to receive eptinezumab,” said Heather Malcolm. This also reflects her hope that eptinezumab will gain regulatory approval for market launch soon—a day that is not far off.

Additionally, Alder is developing ALD1910, a preclinical monoclonal antibody (mAb) designed to inhibit pituitary adenylate cyclase-activating polypeptide (PACAP) for the prevention of migraine. ALD1910 holds potential for preventing migraines in individuals who have an inadequate response to other therapies, thereby offering an alternative treatment option for migraine patients. Alder stated, “ALD1910 is currently undergoing preclinical studies for an Investigational New Drug (IND) application.”

On September 16, 2019, Danish pharmaceutical company Lundbeck and Alder jointly announced that Lundbeck would acquire Alder for $1.95 billion. Lundbeck stated, “We will purchase Alder’s outstanding shares at $18 per share. If eptinezumab receives approval from the European Medicines Agency, Alder shareholders will receive an additional payment of $2 per share.” Lundbeck will finance the transaction through existing cash reserves and bank loans.

The transaction has now been completed. On the first trading day following the acquisition announcement, Alder’s stock price surged by 83%.

“Migraine prevention represents a highly attractive market for us, and we will promote Eptinezumab on a global scale. Meanwhile, we will explore the product’s development potential in other indications,” said Dr. Deborah Dunsire, President and Chief Executive Officer of Lundbeck.

Bob Azelby stated, “Lundbeck has a robust network of neurology experts, is a global leader in neuroscience research, and is an ideal partner. This acquisition will accelerate the global rollout of our migraine medication, eptinezumab, helping more migraine patients worldwide. Additionally, this transaction will expedite the development of our ALD1910 and help us explore new antibody therapies.”

This transaction has also delivered the deserved returns to Alder’s shareholders. After fifteen years of honing our craft, spring has finally arrived; all the dedication and effort have been worthwhile.

Epidemiological studies indicate that the prevalence of migraine in China is 9.3%, affecting a substantial population. Severe migraines can significantly impair patients' daily lives and work performance, potentially leading to loss of labor capacity. Approximately 90% of Chinese migraine sufferers experience headaches on 1 to 14 days per month, while about 10% have headaches on more than 14 days per month. Around 24% of Chinese migraine patients miss more than 20 days of work within a three-month period due to migraines.

Despite the substantial social, economic, and personal burden imposed by migraine, it remains underrecognized in China. China is not a primary market for migraine treatments, and the domestic migraine market is still in its early stages.

Companies planning to enter the migraine field must be prepared for market cultivation. In fact, there are also innovations in migraine treatment in China; for example, Yuefan Medical’s headache patch alleviates migraines through neuromodulation.

If a company plans to develop a new drug, it must be prepared for a “fifteen-year” journey.